In the past, among the compounds having a pyrimidinylpyrazole skeleton, compounds having various physiological activities have been known. For example, pyrimidinylpyrazole compounds having potassium channel modulating activity (Patent Literature 1); the control activity of rice blast, helminthosporium leaf spot of rice plant, powdery mildew of cucumber, etc. (Patent Literatures 2 to 4); and analgesic activity (Patent Literature 5) have been reported, respectively. In recent years, a pyrimidinylpyrazole compound having excellent melanin production inhibiting activity and being useful as a whitening agent has been reported (Patent Literature 6).
Various methods have been known for the formation of a pyrimidinylpyrazole skeleton. In Patent Literature 6, for example, the method wherein a pyrimidinylpyrazole compound is produced by the cyclization reaction of a hydrazinylpyrimidine compound with a β-diketone compound is described.
However, this method is poor in economic efficiency because the hydrazinylpyrimidine compound necessary to obtain the intended pyrimidinylpyrazole compound is not commercially available or, even when it is commercially available, it is very expensive. For the synthesis of a necessary hydrazinylpyrimidine compound, one or two steps are needed and an organic solvent may have to be used as the reaction solvent.
In Non-patent Literature 1, the method wherein a β-methoxyvinyl trifluoromethyl ketone compound is reacted with aminoguanidine bicarbonate in ethanol to form a pyrimidinylpyrazoline skeleton, and it is converted to a pyrimidinylpyrazole skeleton by the subsequent dehydration reaction in dichloromethane is described.
In this method, however, an organic solvent is used as the reaction solvent, and the reaction consists of two steps. In addition, for the synthesis of the raw material, β-methoxyvinyl trifluoromethyl ketone compound, an additional step is necessary.
In Non-patent Literature 2, the method wherein a pyrazole ring is directly introduced by the substitution, in ethanol, of the leaving group of a pyrimidine compound to produce a pyrimidinylpyrazole compound is described.
In this method, a pyrimidinylpyrazole compound can be obtained in one step from two raw materials. However, there are problems in that an organic solvent is used as the reaction solvent, and that the raw materials are very expensive and, if they are synthesized, additional steps are necessary.
Accordingly, from the standpoint of environmental compatibility and economic efficiency, a method wherein a pyrimidinylpyrazole compound can be produced from a small number of raw materials and in a small number of steps, as much as possible, and without the use of an organic solvent, which has a high environmental burden, has been awaited.